1. Field of the Invention
The present invention relates to pharmaceutical compositions useful for the treatment and/or prophylaxis of cardiac diseases. More particularly, it relates to the use of thaliporphine or its derivatives as the active ingredient for the treatment and/or prophylaxis of cardiac diseases.
2. Description of the Related Arts
Recently, the worldwide aged population has been increasing. This is primarily due to improvements in medicine and life-style. However, aging usually is accompanied by an increase of cardiovascular related diseases. Examples include angina pectoris, acute myocardial infarction and coronary artery atherosclerosis, which are associated with the systole and embolism of the vessels. In addition, the embolism of the coronary artery usually results in cardiac hypertrophy, inducing heart failure and arrhythmia. Similarly, cardiac arrhythmia is frequently associated with myocardial ischemia. Malignant ventricular arrhythmias causing collapse is generally believed to be the major mechanism responsible for sudden death. Reperfusion following the release of occluded coronary artery is also associated with arrhythmia. Such arrhythmia may increase the mortality and morbidity of thrombolytic therapy and coronary angioplasty. Several causes for this reperfusion arrhythmia have been proposed. Among them, the generation of oxygen free radicals and their subsequent peroxidation of membrane lipids is perceived as a major cause of reperfusion arrhythmia.
The drugs used for treating patients with heart failure include diuretic, digitalis, vasopressin transferase inhibitor, sympathetic nerve activator or phosphodiesterase inhibitor. Among them, digitalis, sympathetic nerve activator or phosphodiesterase inhibitor can markedly enhance the systole; these drugs however may induce cardiac arrhythmia or tachyrhythmia. Thus, there is no ameliorated effect on the survival of patients by administering those drugs over a long period of time. Recently, an ameliorated effect on the survival of patients with heart failure has been confirmed by administering vasopressin receptor blocker, vasoendotheliosin receptor blocker, and Carvedilol with the blocking activities of sympathetic .alpha.- and .beta.-adrenoceptors, respectively (Ye T L, et al., J. Pharmacol. Exp. Ther., 1992, 263:92-98; Bristow M R, et al., Circulation, 1996, 94:2807-2816; Colucci W S, et al., Circulation, 1996, 94:2800-2806).
Because of the close relationship among occluded coronary artery, heart failure and cardiac arrhythmia, a traditional drug, ouabain, when used as a treatment for heart failure, can enhance the systole, but usually induces cardiac arrhythmia. Thus, the drug is not beneficial to increasing the survival rate of the patients. Therefore, there is still a need to search for the effective agent to suppress arrhythmia, cardiac infarction and the progression of heart failure resulting from an acute coronary attack.
Some compounds have been reported to have the ability to enhance the systole, such as synthetic 2-phenyl-4-oxohydroquinoline (Su M J, et al., Brit. J. Pharmacol., 1993, 110:310-316), thaliporphine of Lauraceae and Rutaceae (Su M J, et al,. Eur. J. Pharmacol., 1994, 254:141-150), liriodenine of Fissistigma glaucescens (Chang G J, et al., Brit. J. Pharmacol., 1996, 118:503-512), (-)-caryachine of Cryptocarya chinensis (Wu M H, et al., Brit. J. Pharmacol., 1995, 116:3211-3218) and berberine derivatives; wherein the liriodenine, (-)-caryachine and berberine derivatives have been confirmed to exhibit antiarrhythmic ability. Conventionally, the effect of antiarrhythmic ability is evaluated by induced arrhythmia using an isolated rat heart subjected to 30 minutes ligation followed by reperfusion. However, the K.sup.+ outward current found in other animals is slightly different from a rat. Therefore, in these trials, guinea pigs were also used as subjects to exhibit this difference in K.sup.+ outward current. In addition, Su et al. (1994, supra) shows that the thaliporphine possesses the ability to enhance systole and Ca.sup.2+ inward currents. Because the enhancement of systole is not beneficial for ischemic myocardial necrosis, drugs with these functions are theoretically useless for treating myocardial infarction and arrhythmia. However, the present invention indeed demonstrates that thaliporphine and its derivatives, particularly in small dosages, are useful for the treatment and/or prophylaxis of cardiac diseases.